MRSA is a significant human pathogen associated with severe infections that are resistant to most antibiotic therapies. Initially MRSA was limited to hospital settings being one of the most common causes of nosocomial infections. However, the emergence of highly virulent community associated MRSA (CA-MRSA) strains has resulted in increased cases in otherwise healthy individuals throughout the population. CA-MRSA strains have caused a pandemic of mostly skin and soft tissue infections, being the most frequent cause of these types of infections reported in emergency rooms throughout the United States [19
]. Although the molecular basis of CA-MRSA virulence has been controversial, it has been documented that CA-MRSA strains have a higher virulence potential, with USA300 being among the most virulent strains [20
In this report, we demonstrate that a conformationally-biased agonist of C5a (EP67) is effective in limiting USA300 infection in a mouse model of dermonecrosis by virtue of its ability to enhance innate immunity. We have previously shown that EP67 induces the release of cytokines IL-6, TNFα, and INFγ, but not IL-2, IL-4, IL-5, IL-10 (Th2 cytokines) from splenic APCs obtained from C57BL/6 mice, and that induction requires the presence of the C5aR CD88 [7
]. Here, we similarly observed that s.c. injection of EP67 resulted in increased production of pro-inflammatory cytokines and chemokines TNFα, INFγ, IL-6, IL-1β, and KC during active bacterial infection. Also, EP67 in the absence or presence of bacteria, promoted the influx of inflammatory infiltrate that included neutrophils, as evidenced by increased levels of MPO and the visual presence of PMNs in skin tissue (). Additional experimentation is required to further determine the exact nature of the infiltrate during infection; however, our results clearly show PMN influx contributes to the EP67-mediated defense, as PMN depletion abrogates the therapeutic effect of EP67 ().
Our results demonstrating that PMNs play an important role in defense against CA-MRSA dermal infection are consistent with previous findings [21
] as neutrophils are a critical component of the innate immune response during MRSA infection [22
]. However, it has been well documented that MRSA is capable of resisting innate immunity, and specifically PMN killing, by various mechanisms [23
]. Thus while additional experimentation is required to further elucidate specific mechanism(s) of EP67-mediated immune enhancement during infection, we speculate that EP67 engagement of APC populations results in cytokine/chemokines mediator release, and subsequent PMN recruitment to the infection site.
It is apparent that with the emergence of antibiotic resistant organisms, therapeutic approaches beyond the development of new antibiotics modalities need to be addressed. The activation of innate immunity is critical step for the control of problematic bacterial infections. Our data suggest that prophylactic use of EP67 may be advantageous for individuals at high risk of developing MRSA infection, such as those with wounds or burns. While further experimentation is required to determine if EP67 can be used to treat an established infection, our data support the continued investigation and advancement of EP67 as a candidate immunotherapeutic for CA-MRSA infection.